Molecular Basis for Arrhythmias: Role of Two Nonsarcolemmal Ion Channels

Molecular Mechanisms for Arrhythmias . Ventricular tachycardia/fibrillation and sudden cardiac death occur frequently following myocardial ischemia or infarction. The recent Cardiac Arrhythmia Suppression Trial (CAST Study) found that patients treated with the Na‐channel antagonists encainide and flecainide suffered increased mortality over placebo. This unexpected result has dampened enthusiasm for treatment of asymptomatic ventricular arrhythmias and more subtly suggests a need for review of current strategies for analysis and treatment of cardiac arrhythmias. This article focuses on two nonsarcolemmal ion channels that may be involved in certain types of ventricular arrhythmias: the gap junction channel and the Ca 2+ ‐release channel of sarcoplasmic reticulum (SR). Gap junctions enable conduction of the cardiac impulse from cell‐to‐cell and may be involved in reentrant arrhythmias. SR Ca 2+ ‐release channels regulate the level of cytosolic Ca 2+ during initiation of contraction and seem to be the basis for triggered activity. Gap junction and SR Ca 2+ ‐release channels, though structurally dissimilar molecules, share certain functional and gating characteristics. In different ways, both channels couple the electrical response to the mechanical response. Furthermore, dysfunction of gap junction channels and/or SR Ca 2+ ‐release channels may underlie the development of arrhythmias in postischemic cells. Classification of arrhythmias on the basis of which channel(s) is principally involved might expedite the development of new drugs targeted at functional regions of the chan‐nel(s). Ultimately, pharmacotherapy of arrhythmias directed at the molecules responsible for the electrical dysfunction may replace the empirical approach that dominates current cardiology practice. ( J Cardiovasc Electrophysiol, Vol. 1, pp. 464–480, October 1990 )